This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. New evidence suggests that autistic disorder (AD) may be associated with abnormalities in folate metabolism, which is a process that affects genetic expression by facilitating the formation of methyl donors for DNA methylation. Limited data show that some children with AD show behavioral improvements with folic acid (FA) therapy, while others show a worsening effect. If behavioral worsening is linked with abnormalities in folate metabolism, then nutritional modifications could normalize these processes and result in clinical improvements. To address this premise, we propose a randomized, placebo-controlled crossover pilot study with two phases. The first phase will focus on the behavioral and biochemical responses of children with AD to high-dose folic acid supplementation. Because FA is an inactive folate that requires biochemical conversion to become active, and select genotypes impede this conversion, our general hypothesis is that FA will yield behavioral improvements in some children but exacerbate problem behaviors in others. During the second phase, children who had a worsened behavioral response to FA during phase 1 will participate in an open-label trial of high-dose Metafolin[unreadable][unreadable] supplementation. The focus here would similarly be on the behavioral and biochemical outcomes of participating children following treatment with the study supplement. Because Metafolin[unreadable][unreadable] is an active folate metabolite that should not be affected by genotypes in the folate pathway, our general hypothesis for phase 2 is that Metafolin[unreadable][unreadable] would yield behavioral improvements without the risk for behavioral worsening. Results from this project may provide support for continued study of the potential relationship between folate metabolism and problem behaviors among children with AD, potentially justifying the need to examine effects of folate supplementation among a larger sample of affected children. Autistic Disorder (AD): Autism is a neurodevelopmental disorder that presents as deficits in both social and communication skills alongside repetitive, stereotypic behaviors. Developmental delays and/or abnormal functioning in at least one of these three areas must have been present prior to age 3. Approximately 75% of children diagnosed with autism also meet criteria for mental retardation, functioning in the moderately affected range (IQ between 35[unreadable]??50), and seizures may occur in up to 25% of cases (1). Males are diagnosed with AD approximately four times as often as are females. Based on data available as of 2002, surveillance estimates indicate that 1 of every 150 children is diagnosed with an autism spectrum disorder (2). There is no substantiated cause for the majority of individuals with AD;however, the influence of genetics in the development of this disorder is well established. Twin studies reveal concordance rates around 5% for dizygotic twins and between 60% and 90% for monozygotic twins when the diagnostic criteria are more narrow or more broad, respectively (3, 4). The recurrence risk for non-twin siblings is between 3% and 5% (5), which is substantially higher than that for the general population. Moreover, AD has been described in association with various genetic conditions, including: tuberous sclerosis, Angelman syndrome, Smith-Lemli Opitz syndrome, Down syndrome, MECP2 mutations, 22q13 deletion, duplications of 15q11-q13, supernumerary isodicentric 15q chromosomes, and fragile X syndrome (6, 7). More recently, there is evidence that a larger fraction of autism patients have de novo chromosomal deletions or duplications (8, 9).